Abstract
Adult T-cell Leukemia (ATL) is a lymphoproliferative disease of CD4+ T-cells infected with Human T-cell Leukemia Virus type I (HTLV-1). With the exception of allogeneic hematopoietic stem cell transplantation, there are no effective treatments to cure ATL, and ATL cells often acquire resistance to conventional chemotherapeutic agents. Accumulating evidence shows that development and maintenance of ATL requires key contributions from the viral protein, HTLV-1 basic leucine zipper factor (HBZ). In this study we found that HBZ activates expression of Heme Oxygenase 1 (HMOX-1), a component of the oxidative stress response that functions to detoxify free heme. Transcription of HMOX1 and other antioxidant genes is regulated by the small Mafs. These cellular basic leucine zipper (bZIP) factors control transcription by forming homo- or heterodimers among themselves or with other cellular bZIP factors that then bind Maf responsive elements (MAREs) in promoters or enhancers of antioxidant genes. Our data support a model in which HBZ activates HMOX1 transcription by forming heterodimers with the small Mafs that bind MAREs located in an upstream enhancer region. Consistent with this model, we found that HMOX-1 is upregulated in HTLV-1-transformed T-cell lines and confers these cells with resistance to heme-induced cytotoxicity. In this context, HBZ-mediated activation of HMOX-1 expression may contribute to resistance of ATL cells to certain chemotherapeutic agents. We also provide evidence that HBZ counteracts oxidative stress caused by two other HTLV-1-encoded proteins, Tax and p13. Tax induces oxidative stress as a byproduct of driving mitotic expansion of infected cells, and p13 is believed to induce oxidative stress to eliminate infected cells that have become transformed. Therefore, in this context, HBZ-mediated activation of HMOX-1 expression may facilitate transformation. Overall, this study characterizes a novel function of HBZ that may support the development and maintenance of ATL.
Highlights
The accumulation of reactive oxygen (ROS) and nitrogen species (RNS) is known to induce damage to cellular structures, including genetic material
One approach is to target functions of one of the proteins produced by the virus, known as HTLV-1 basic leucine zipper factor (HBZ), which is believed to contribute to the development of Adult T-cell Leukemia (ATL) and to the survival of leukemic cells in ATL patients
We found that HBZ increases the expression of the cellular enzyme, Heme Oxygenase 1 (HMOX-1), which plays a central role in curbing oxidative stress
Summary
The accumulation of reactive oxygen (ROS) and nitrogen species (RNS) is known to induce damage to cellular structures, including genetic material. Oxidative DNA damage can result in cell cycle arrest, the induction of replicative senescence, and initiation of apoptosis [1]. To avoid these outcomes, expression of free radical- and metal-scavenging enzymes is induced in response to oxidative stress as a means of limiting cellular damage. Nrf and small Mafs form heterodimers that activate transcription of antioxidant genes by binding various types of antioxidant response elements (AREs) located in the promoters and/or enhancers of these genes [2, 3]. Chromatin immunoprecipitation-deep sequencing (ChIP-Seq) analyses of Nrf and MafG genomic binding sites that Nrf2/small Maf heterodimers frequently occupy sites containing the sequence 5’-TGCTGA[C/G]TCAGCA-3’, termed Maf recognition elements (MAREs)[4,5,6]
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